Destruction of lymphatic vessels during the treatment of breast cancer by surgery and/or radiation therapy can lead to the development of secondary lymphedema. The breast-cancer-related lymphedema is associated with debilitating limb swelling, chronic inflammation, tissue fibrosis, and increased susceptibility to infection. It has been estimated that approximately 20% of the 2.3 million breast cancer survivors in the US suffer this chronic condition following axillary lymph node dissection and radiation therapy. Current treatments for secondary lymphedema are limited to lifelong physiotherapies, which can cause substantial and even prohibitive financial, physical, and psychological strain for most patients. Clearly, there is an unmet yet urgent medical need for new approaches to treat lymphedema in breast cancer survivors. Interestingly, recent discoveries have shown that two human hormones-adrenomedullin (ADM) and intermedin (IMD/ADM2)-and their cognate receptors (CLR/RAMP1, 2, and 3 receptors) play critical roles in the regulation of lymphangiogenesis and endothelial permeability, and that adipose tissue-derived progenitor cells (ADRCs) can promote lymphatic vessel formation in lymphedema models. Because breast cancer survivors may be deprived of endothelial progenitor cells that are essential for the regeneration of lymphatic vessels, we hypothesize that a combination therapy that integrates a CLR/RAMP receptor ligand and ADRCs could be the most efficient approach to prevent the occurrence of or to reduce the debilitating effects of lymphedema. To realize the full potential of this combination therapy, a group of stable ADM and IMD analogs that exhibit prolonged bioactivity in vivo have been developed. Accordingly, we propose to investigate the potency of combination therapies that comprise ADRCs and select stable analogs in improving the regeneration of lymphatic vessels in a mouse secondary lymphedema model. Successful development of this novel combination therapy has the potential to decrease the debilitating effects of breast-cancer-related lymphedema among breast cancer survivors.